Wilson Disease (WD) Overview:

• Cause: Mutation in the ATP7B gene (autosomal recessive), which encodes a copper-translocating ATPase, primarily found in the liver.
• Pathophysiology: Leads to progressive, toxic copper accumulation in the body.
• Onset: Copper accumulation begins in infancy with the introduction of copper-rich foods.
• Organ Involvement: Copper deposits in liver, kidneys, heart, nervous system, and cornea.
• Importance of Early Diagnosis: Prevents liver failure and irreversible brain damage.

Genetic Considerations:

• Inheritance: Autosomal recessive.
• Sibling Risk: Siblings of WD patients have a 25% chance of developing clinical symptoms.
• Family Screening:
• All siblings should be screened (examination, labs incl. liver function and ceruloplasmin, ATP7B gene analysis).
• Parents should be screened due to possible late-onset WD.

Clinical Presentation:

• Children (over 1 year): Increased serum transaminases are a common first symptom, hepatomegaly, abnormal liver imaging (hyperechogenic liver on ultrasound), liver failure, and cirrhosis.
• Adolescents/Young Adults: Psychiatric and neurologic symptoms, but mild cognitive impairment can be seen earlier.
• Kayser-Fleischer Rings: Copper deposits on the Descemet membrane of the cornea, seen on slit-lamp exam (usually present in children over 10, often associated with neurological involvement).
• Less Common Presentations: Hemolytic anemia, renal disease, pancreatitis, cardiac disease, hypoparathyroidism, and rickets.

Diagnosis:

• Evaluation of Copper Metabolism:
• Liver function tests (elevated in advanced disease, high bilirubin with relatively mild transaminase elevation common).
• Low alkaline phosphatase to total bilirubin ratio can be indicative of WD.
• Ceruloplasmin: Usually <10 mg/dL (<171.1 µmol/L) in WD (normal 20-40 mg/dL (342.1-684.2 µmol/L)). (May be falsely elevated in active hepatitis).
• Total Serum Copper: Helpful for monitoring treatment response, not always helpful for diagnosis.
• 24-Hour Urinary Copper Excretion: >100 µg suggests WD (reference range, <40 µg).
• ATP7B Gene Mutation Analysis: Very useful, particularly in family members; confirms >95% of carriers (including heterozygotes) as over 500 mutations have been identified to date.
• Liver Biopsy: Needed if other tests are inconclusive; >250 µg/g dry weight indicates WD (normal <50 µg/g dry weight).

Treatment:

• Dietary Copper Restriction: Avoid nuts, chocolate, mushrooms, shellfish, and organ meats.
• Chelating Agents (start by age 2-3):
• D-Penicillamine: First-line; chelates copper and is excreted in urine. Adverse reactions are common.
• Trientine: Second-line (for those intolerant to D-penicillamine), but some use as first-line.
• Zinc Salts:
• First-line for pre-symptomatic pediatric patients.
• Blocks copper absorption in the intestinal tract.
• Monitor serum/urine copper to titrate dose and assess compliance.
• Monitoring: Serum and urinary copper levels are monitored.
• Current Limitations: Treatments control symptoms but don't cure the disease. Chelators have significant side effects; zinc may fail in adults over time. Psychiatric symptoms may progress despite treatment.

Advanced/Experimental Therapies:

• Liver Transplantation: Curative, but with complications and lifelong immunosuppression; reserved for life-threatening cases.
• Alternative Therapeutics (in development): Cell therapy and/or gene therapy to target specific ATP7B mutations.

Notes:

*Decreased ceruloplasmin is not diagnostic because it can be seen in other conditions as well: malabsorption, glycosolation defects, Menkes, nephrotic syndrome, acquired copper deficiency, hereditary aceruloplasminemia. In fact some patients with Wilson Disease may even have elevated ceruloplasmin: Chronic active hepatitis, infection/inflammation, or pregnancy

Also note: liver copper content is physiologically increased in infancy until about 14mo